RO120261B1 - Process for the selective preparation of z-isomer of 3-(2-substituted vinyl)cephalosporin - Google Patents

Abstract

The invention relates to a process for selective and high-yield preparation of the Z-isomer of a 7-N-unsubstituted or substituted amino-3-[2-(4-thiazol-unsubstituted or substituted-5-yl]vinyl]-3-cephem-4-carboxylic acid or an ester thereof, represented by the general formula (IV):.

Description

The present invention relates to a process of selective and high yield preparation of the Z isomer (cis isomer) of the cephalosporin antibiotic having a 2- (4-thiazolsubstituted or unsubstituted-5-yl) vinyl group as a substituent at the 3-position, or the Z-isomer ( c / s) isomer of a 7-amino-3- [2- (4-thiazol-substituted or unsubstituted-5-yl) vinyl] -3-cefem-4-carboxylic acid, or a protected derivative thereof used as an intermediary for the synthesis of the so-called cephalosporin antibiotic. This invention also relates to a process for the efficient, easy and high-purity preparation of the Z isomer (c / s isomer) of a 7- [2- (2-aminothiazol-4-yl) -2 acid. -alkoxyiminoacetamido] -3- [2- (4-thiazol-substituted or unsubstituted-5-yl) vinyl] -3-cefem-4-carboxylic acid, or a 7-amino-3- [2- (4-thiazole acid) -substituted or unsubstituted-5-yl) vinyl] -3-cefem-4-carboxylic acid, or has a protected derivative thereof.

Japanese patent publications Hei 3-64503 (JP 1698887) or US Patent Nos. 4839350 or EP 0175610, correspondingly, describe 7- [2-methoxyimino-2- (2-amino-thiazol4-yl) acetamido] -3- [2- (4-methylthiazol-5-yl) vinyl] -3-cefem-4-carboxylic acid (sin isomer, isomer c / s) represented by the following formula (A):

This compound is an excellent cephalosporin antibiotic, called cefditoren. The excellent antibacterial activity of cefditoren against gram-negative bacteria is attributed to the fact that the cefditoren compound has the Z configuration, so that the cefem ring and the 4-methylthiazol-5-yl group of cefditoren are linked in this c / s configuration to the carbon-carbon double bond. of the 3-vinyl group of the cefditorene molecule.

7- [2-Methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- [2- (4-methylthiazol-5-yl) vinyl] -3 pivaloyloxymethyl ester (sin isomer, cis isomer) -cefem-4-carboxylic acid obtained by esterification of the 4-carboxyl group of the above-mentioned cefditorene compound with the pivaloyloxymethyl group is represented by the following formula (B):

O and is a pro-drug with the general name pivoxil cefditoren (reference in Merck Index ”, edition 12, page 317). In the case of cephalosporin antibiotics of the type 3- (2-vinyl-substituted) it is generally known that the Z isomer (c / s isomer) has antibiotic properties superior to the E (trans isomer).

RO 120261 Β1

The aforementioned 3- (2-vinyl-substituted)-cephalosporin antibiotics, including cef- 1 ditorene, or intermediates used for the synthesis of said antibiotics, can be prepared by various processes. One of the known processes for the preparation of these antibiotics 3 is the process using the Wittig reaction. Such a process for preparing 3- (2-vinyl-substituted) -cephalosporin antibiotics or intermediates for their synthesis, which comprises using the Wittig reaction, is described, for example, in the first publication of the Japanese KOKAI Hei-3 patent application. -264590, or US 5233035 or EP 0175610 A2, correspondents; 7 Journalof AntibioticsXUW, no. 8, pp. 1047-1050 (1990), Chem. Pharm. Bull., You. 39, no.

9, pages 2433-2436 (1998) and international publication WO 95/09171 (published April 6, 9 1995) of application PCT / JP94 / 01618, or corresponding EP 0734965 A1. By performing the Wittig reaction step, according to the prior art processes, the resulting reaction product was always obtained as a mixture of the Z isomer and the E. isomer.

For example, Journal of AntibioticsXLIII, no. 8, pp. 1047-1050 and Chem. Pharm. 13 Bull., You. 39, no. 9, pages 2433-2436, mentioned above, describes a process for the preparation of such 7-p-phenylacetamido-3- [2- (4-methylthiazol-5-15-yl) vinyl] -3- ester 4-methoxybenzyl acid. cefem-4-carboxylic acid which can be used for the synthesis of 7 - [(Z) -2- (2-aminothiazol-4-yl) -2-methoxyimino-acetamido] -3 (Z) - (4-methylthiazole-5- il) vinyl-3-cefem-4-carboxylic acid, mentioned above. In this process, the steps of treating the p-methoxybenzyl ester of 7-p-phenylaceae tamido-3-chloromethyl-3-cefem-4-carboxylic acid with sodium iodide, 19 in acetone, are obtained to obtain the corresponding 3-iodomethyl derivative. ; treating this derivative with triphenylphosphine to obtain the appropriate triphenylphosphonium iodide; and reaction of this 21 triphenylphosphonium iodine with 5-formyl-4-methylthiazole by Wittig reaction, at room temperature, in a heterogeneous reaction medium, comprising dichloromethane (methylene chloride) and water, in the presence of sodium bicarbonate, for thus obtaining 7-P-phenylacetamido-3- [2- (4-methylthiazol-5-yl) vinyl] -3-cefem-4-carboxylic acid 4-methoxy benzyl ester. 25

The process mentioned above can be expressed by the following reaction scheme:

RO 120261 Β1

NaHCO _s

CHO

In the above-mentioned process, the methoxy-1-benzyl ester 4-p-phenylacetamido-3 - [(triphenyl-phosphoranylidene) methyl] -3-cefem-4-carboxylic acid 4 is obtained in the above-mentioned process. Formula (F) above, which is then reacted with 5-formyl-4-methylthiazole by Wittig reaction 3 to obtain 7-3-phenylacetamido-3- [2- (4-methylthiazol-5-yl) 4-methoxybenzyl ester. ) vinyl] -3-cefem-4-carboxylic acid of formula (H). The reaction product of formula (H) was obtained, as described in the literature mentioned above, in the form of a mixture of Z isomer (cis isomer) and E (trans isomer) of compound (H) in a ratio mixing 7 4.7: 1.

The aforementioned Journal of Antibiotics describes the fact that the Z and E isomers in the mixture of 9 of the compound of formula (H) are difficult to isolate from each other even by a treatment technique on a chromatographic column. Further, the aforementioned literature describes that the Z isomer of the target product can be isolated only by applying a method comprising removing the 7-phenylacetyl group from the compound of formula (H) by a deprotection technique, condensing the position 7 of the product deprotected with 2- (2-tritylaminothiazol-4-yl) -2-methoxyimino-acetic acid, deprotection reaction of the product resulting from condensation, then chromatography on a column with a porous nonionic resin of the resulting deprotected product, and in further fractional crystallization of the resulting product thus purified. In this way, the yield 17 in the Z isomer desired as finally harvested was considerably lower.

In addition, the first publication of the Japanese patent application KOKAI Hei-7-188250, or US 19 5616703, or corresponding EP 658558A1, discloses that the reaction product, which comprised 7-amino-3- [2- (4 -methylthiazol-5-yl) vinyl] -3-cefem-4-carboxylic acid, or a derivative thereof having the following formula (J):

COOR27 wherein, R is a sily or hydrogen atom protecting group and which was obtained by the Wittig reaction, is a mixture of the Z isomer and the E. isomer. The first publication of the Japanese patent application KOKAI Hei-7 -188250 also discloses a method for isolating the Z-31 isomer comprising transforming the Z / E mixture of 7-amino-3- [2- (4-methylthiazol-5-yl) vinyl] -3-cefem-4 -carboxylic acid in a suitable amine salt and recrystallization of the 33 amine salt thus obtained. This publication further describes that when the above Z / E mixture is subjected to chromatography, the Z isomer can be obtained from which the lower activity E isomer has been removed as much as possible.

In addition, international publication WO95 / 09171 describes a process comprising steps of treating a phosphonium halide represented by the following formula (K):

RO 120261 unde1 where X is CH or N, R ¹¹ is an amino group or a protected amino group, R ¹² is a hydrogen atom or a hydroxyimino protecting group, R ¹³ is a hydrogen atom, a salt-forming cation, or a protecting group of the carboxyl group, R ¹⁶ is an aryl group, for example, a phenyl group and W is a halogen atom, with a base, such as sodium bicarbonate, in acetone, tetrahydrofuran, methylene chloride or water, at room temperature, to obtain a compound, tri-arylphosphoranilidene, represented by the following formula (L):

where R ¹¹ , R ¹² , R ¹³ and R ¹⁶ have the same meanings as above, then the reaction of the compound of formula (L) with a 4-thiazole-substituted or unsubstituted-5-carbaldehyde with the following formula

Where R ¹⁴ is a hydrogen atom, R ¹⁵ is a hydrogen atom, a lower alkyl group, a halogenated lower alkyl group, or a halogen atom, by Wittig reaction, at room temperature, or with methylene chloride cooling. , methylene chloride-water, tetrahydrofuran, or dioxane, to obtain a 3-vinyl-cefem compound represented by the following formula (N):

where R ¹¹ , R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ have the same meanings as above. In this prior art process, the resulting reaction product comprising the 3-vinyl-cefem compound of formula (N), thus obtained by reacting the phosphoranilidine compound of formula (L) with the aldehyde compound of formula (G ') by Wittig reaction, was also in the form of a mixture of Z isomer (c / s isomer) and E (trans isomer) of compound (H). To isolate and recover the desired Z-isomer from the 3-vinyl-cefem compound of formula (N) it was necessary for the above-mentioned process that the reaction solution thus obtained by the Wittig reaction step was first washed with an aqueous chloride solution. of sodium, then dried over anhydrous magnesium sulfate and further concentrated under reduced pressure and the resulting concentrated residue is purified by chromatography so as to separate the Z isomer from the E isomer. Thus, in this process from the prior art, the yield in The desired Z-isomer of the 3-vinyl-cefem compound of formula (N) was also unsatisfactory. Through the processes of the prior art,

In order to obtain the 3-vinyl-cefem compound comprising the use of the Wittig reaction, no previous case can be found in which the lower alkanol is used in the reaction medium of the Wittig reaction. 3

Therefore, if the process for the preparation of a cephalosporin compound having the vinyl group 3- [2- (4-substituted or unsubstituted-thiazol-5-yl)], which comprises the reaction of such an acid 7- [2, has been carried out - (2-Aminothiazol-4-yl) 2-alkoxyimino-acetamido] - [3 (phosphorus-allylidene-trisubstituted) -methyl] -3-cefem-4-carboxylic acid, or an ester thereof, as shown 7 by the compound of formula (L) above, or a 7-amino or 7-Namino-protected-3 - [(phosphoranylidene-trisubstituted) methyl] -3-cefem-4-carboxylic acid, or a 9-ester. it with a 4-thiazole-substituted or unsubstituted-5-carbaldehyde of formula (G '), by Wittig reaction, was requested to provide such a process for the preparation of compounds 11 3- (2-vinyl-substituted) - cephalosporins that would be able to selectively produce the desired Z isomer (c / s isomer) of cephalosporinic 3- (2-vinyl-substituted) compounds in a significantly greater proportion than the undesirable E (trans isomer) di isomer. In cephalosporinic 3- (2-vinyl-substituted) compounds.

Also, another application was requested to provide a new process for the preparation of 3- (2-vinyl-substituted) cephalosporins that might be able to recover the desired Z-isomer from the high-yielding, high-purity cephalosporin final product directly from the 17 solution. of the reaction resulting from the Wittig reaction, without involving any specific purification step for separating the desired Z isomer from the E isomer, thus formed. In the prior art, the processes for the preparation of 3- (2-vinyl-substituted) cephalosporin, which includes the use of the Wittig reaction, have such disadvantages that the selectivity of prepara- tion of the Z isomer is lower compared to that of the E isomer, that the isolation of the Z isomer. the E-isomer required some additional complicated operations, and the actual yield of the Z-isomer is unsatisfactorily low.

In addition, performing the prior art procedures, the conventional process was used, so that the Wittig reaction step was performed using as the reaction medium, substantially in all cases, methylene chloride or methylene chloride-water and with use as a temp. 27 room temperature reaction rate.

The inventors carried out laborious investigations with the intention of providing such a process for the preparation of 3- (2-vinyl-substituted) cephalosporins that would eliminate the shortcomings of the prior art processes, as mentioned above. Concentric studies, 31 in particular, the reaction medium, reaction temperature and other reaction conditions that are available for the Wittig reaction have been studied. As a result, it has now been surprisingly found that if 33 is used as a medium for the Wittig reaction a mixed solvent consisting of a mixture of chlorinated hydrocarbon solvents with a lower alkanol at a certain mixing ratio (in volume and if used simultaneously as a temperature for the Wittig reaction, a temperature of 5'C or lower, preferably 0 "C ~ -50 ° C, it is feasible to produce the desired 3- (2-) Z isomer. vinyl-substituted) cephalosporin significantly higher than the undesirable E isomer in the reaction solution of the Wittig reaction, so that the selectivity of preparation of the desired Z isomer is thereby enhanced and the yield in the Z isomer is increased. the basis of these discoveries was the invention

According to a first aspect, the invention relates to a p rocede of selective preparation of the Z isomer of a 7-N-unsubstituted or substituted-amino-3- [2- (4-thiazole-unsubstituted 43 or 5-yl) acid. vinyl] -3-cefem-4-carboxylic acid or an ester thereof represented by the following general formula (IV): 45

RO 120261 Β1 (IV)

wherein, R ¹ means a hydrogen atom or a monovalent protecting group of the amino group, or R ¹ means a 2- (2-N-protected or unprotected-aminothiazol-4-yl) -2-alkoxyminoacetyl group having the following formula ( II):

where, R ⁵ is a hydrogen atom or a monovalent protecting group of the amino group and R ⁶ is a hydrogen atom, or R ⁵ and R ⁶ taken together means a divalent protecting group of the amino group and R ⁷ is an alkyl group with 1-4 carbon atoms, and in which, R ² means a hydrogen atom, or R ¹ and R ² taken together mean a divalent protecting group of the amino group and R ³ means a hydrogen atom, a pivaloyloxymethyl group or a group forming an ester as the protecting group of the carboxyl group, and R ⁸ means a hydrogen atom, an alkyl group with 1-4 carbon atoms, a trifluoromethyl group or a chloro group, characterized in that said process comprises the reaction of an acid 7. -N-unsubstituted-substituted-amino-3 - [(trisubstituted-phosphoranylidene) methyl] -3-cefem-4-carboxylic acid, or an ester thereof represented by the following general formula (I):

where each R ¹ , R ² and R ³ has the same meaning defined as above and R ⁴ means an alkyl group with 1 ~ 6 carbon atoms or an aryl group, or a compound represented by the following general formula (Γ):

RO 120261 Β1

wherein each R ¹ , R ² , R ³ and R ⁴ has the same meaning as defined above, with an unsubstituted or substituted 4-thiazole-1-5-carbaldehyde represented by the following formula (III):

_R s (III) 5

CHO 7 where R ⁸ has the same meaning as defined above, in a solvent mixture consisting of 9 of one or more chlorinated hydrocarbons and one or more alkanols mixed in a mixing ratio (by volume) of 1: 3 up to 1: 0.25, at a temperature of + 5 ° C to 11 -50 ° C.

The process according to the first aspect of this invention differs from the processes of the aforementioned prior art 13 for the preparation of 3- (2-substituted-vinyl) cephalosporins using the Wittig reaction, in that the process of this invention uses such reaction medium 15 as such. a solvent mixture obtained from a mixture of chlorinated hydrocarbon solvents (s) with lower alkanol (s) in a specific mixing ratio, and by the process of this invention using as a reaction temperature a temperature of 5'C or lower. However, the process of this invention with respect to other reaction processes 19 and the reaction conditions with respect to those of prior art processes do not differ significantly. Despite these minor differences from prior art processes, the process of the present invention may result in obtaining the desired Z isomer of cefem compounds of formula (IV) with higher selectivity and higher yield than the E. isomer. 23 was totally unexpected.

The compound of general formula (I) which is used as starting material in process 25 according to the first aspect of this invention may be prepared by a method comprising the steps of (i) treating 3-halomethyl-3-cefem with the following general formula ( V): 27

wherein R ¹ , R ² and R ³ each have the same meanings as defined above and W is a chlorine atom or a bromine atom, with sodium iodide or potassium iodide in a reaction medium, for example, acetone or a mixed solvent obtained from a mixture of methylene chloride, or chloroform, with water, at room temperature, to obtain 3-iodomethyl-3-cefem compound with the following general formula (VI):

RO 120261 Β1 where R ¹ , R ² and R ³ each have the same meanings as defined above; (ii) reaction of the compound of formula (VI) with trialkylphosphine or triarylphosphine with the following formula (VII):

(VII) wherein R ⁴ is an alkyl group of 1-6 carbon atoms, preferably a straight chain alkyl group or an aryl group, preferably a phenyl group, or a phenyl group substituted with (C 1 -CJ) alkyl in reaction medium of the same type as that used in step (i) above, at room temperature, to obtain a methyl-phosphonium trialkyl (or aryl) compound of general formula (VIII):

R *

® © (VHI) where R ¹ , R ² , R ³ and R ⁴ each have the same meanings as defined above; and (iii) reaction of the methyl phosphonium compound of formula (VIII) with an aqueous solution of a base, such as sodium bicarbonate or sodium hydroxide, in a reaction medium obtained, for example, from methylene chloride or chloroform -water, at room temperature, or ice-cold, to obtain the phosphoranilidine trialkyl (or aryl) compound of general formula (I) presented above. As a starting material it can be used instead of the compound of general formula (I) above, the compound of general formula (I ') - It is convenient that the reaction solution that was obtained in step (iii) above and containing the compound with the general formula (I) to be used as such directly in the process of this invention, so that the process of this invention can continue as a single-step process ", without separating the compound of general formula (I) from the reaction solution of that step (iii) preparation of compound (I).

In the compound of general formula (I) or (I ') used as starting material, the amino-mono-valent protecting group, which may be represented by R ¹ and (or) R ⁵ , has no special limitation, as far as which amino-protecting group is conventionally used in the synthesis of penicillin and cephalosporin compounds.

Examples of such amino-mono-valent protecting groups may be listed as monosubstituted (or di- or trisubstituted) or unsubstituted phenyl-alkyl groups, for example, the benzyl group, the benzhydryl group, the trityl group; an alkanoyl group such as, for example, the formyl group, the acetyl group; lower alkoxycarbonyl group, for example methoxycarbonyl group; an aryl acyl group, for example, benzoyl group, tolyl group; heterocyclic carbonyl group, for example, thiazolylcarbonyl group, tetrazolylcabonyl group; an alkanoyl group substituted with an aryl or aryloxy group, for example, phenylacetyl group, phenoxyacetyl group; an aralkyloxycarbonyl group, for example, the benzyloxycarbonyl group; or an alkanoyl group substituted with a heterocyclic group, for example, the imidazolylacetyl group, the thiazolylacetyl group; and the like. The pheniacetyl group is particularly preferred as an amino protecting group. In cases where R ¹ and R ² or R ⁵ and R ⁶ taken together mean an amino-divalent protecting group, examples of such amino-divalent protecting groups are a substituted or unsubstituted aralkylid group, for example, benzylidene group, salicylidene group , or the tetrahydro-pyranylidene group.

In addition, in such compounds of the general formula (I) or (I '), where R ³ represents an ester-forming group such as the carboxyl-protecting group, such a group

Ester forming an ester has no special limitation, to the extent that such a carboxyl-protecting group 1 is available at position 3 or position 4 of penicillins and cephalosporins in their synthesis. As such groups which form an ester for R ³ may be exemplified by a lower alkyl group, for example, methyl group, ethyl group, f-butyl group; a lower alkenyl group, for example, the vinyl group, the allyl group; lower alkoxyalkyl group, for example, methoxymethyl group, ethoxymethyl group; lower alkylthioalkyl group, for example methylthiomethyl group, ethylthiomethyl group; the lower alkanoyloxyalkyl group, for example 7, the acetoxymethyl group, the butyloxymethyl group; monosubstituted (or di- or trisubstituted) phenylalkyl group, or unsubstituted, for example, benzyl group, 4-9 methoxybenzyl group, benzhydryl group, trityl group and the like. Particularly preferred as the carboxyl-protecting group is the 4-methoxybenzyl group. Additionally, R ⁴ represents a lower alkyl group or an aryl group. For R ⁴ , the lower alkyl group may be an alkyl group of 1-6 carbon atoms, in particular the methyl, ethyl group, propyl group, n- or t-butyl group. Particularly preferred is the n-butyl group. For R ⁴ , as the aryl group, the phenyl group is preferred. 15

Examples of solvents based on chlorinated hydrocarbon, which are a mixture of solvents to be used as the reaction medium in the process according to the first aspect of this invention, include monochloro-, dichloro-, or trichloroalkane (C ~ C ₂ ), preferably methylene chloride (respectively, dichloromethane), or chloroform, or dichloromethane, or a mixture of two or more of them.

The other component of the solvent mixture to be used in process 21 of this invention is a lower alkanol. The lower alkanol may include an alkanol of 1 ~ 6 carbon atoms, preferably methanol, ethanol, n-propanol, isopropanol, n-butanol, or t-23 butanol, or a mixture of two or more of them. The particularly preferred solvent mixture to be used is a mixture consisting essentially of chloroform and 25 n-propanol.

In the process according to this invention, a mixture of 27 solvents obtained from a mixture of chlorinated hydrocarbon solvents (s) with the alkanol solvent (s) is used as a reaction medium in a mixing ratio ( in volume) in a range of 29 1: 3 to 1: 0.25. It is desirable to use such a mixture of solvents obtained by mixing chlorinated hydrocarbon with alkanol, having the mixing ratio, preferably, in the range of 1: 1 to 1: 0.28, in particular 1: 0. , 5 to 1: 0.4. When the ratio of mixing of the chlorinated hydrocarbon with the alkanol present in the solvent mixture thus used 33 is outside the range of 1: 3 to 1: 0.25, the amount of the isomer E obtained increases, while the amount of the isomer Z thus produced decreases. . The reaction temperature used also strongly influences the amount of the Z isomer thus produced. In the process of this invention, the reaction is carried out at a reaction temperature in the range of + 5 ° C to 37 -50'C, in particular O'C to -50 ° C. When the reaction is carried out at a temperature in the range -1 O'C to -30'C, the amount of the E isomer thus obtained decreases considerably, and the quantity 39 of the Z isomer thus obtained can be greatly improved compared to that of the E isomer. 41

Good results are obtained if the process according to the first aspect of this invention is carried out in such a way that the mixing ratio (by volume) of the solvent 43 based on chlorinated hydrocarbon and the lower alkanol in the solvent mixture thus used is determined in range 1: 1-1: 0.28, more preferably in the range 1: 0.5-1: 0.4 and also 45 when the reaction of the compound of formula (I) (or Γ) with a compound of formula (III ) is carried out at a temperature in the range -1O'C ~ -3O ° C, preferably -18'C ~ -23 ° C. In addition, such a result is obtained that the amount of Z isomer obtained is remarkably improved

In comparison with that of the isomer E, when the process according to the first aspect of this invention is carried out in such a way that the reaction is conducted in a mixture of solvents consisting of chloroform or dichloromethane and n-propanol, in a mixing ratio ( in volume) in the range 1: 0.25-1: 0.4, at temperatures in the range -18 ° C ~ -23 ° C.

The process according to the first aspect of this invention can conveniently be carried out by dissolving the compound of formula (I) or (Γ) in the solvent mixture thus used; cooling the resulting solution to a required reaction temperature; adding to the cooled solution a carbaldehyde of formula (III) in a required amount stoichiometrically or in excess or in excess; stirring the resulting reaction mixture while maintaining the reaction mixture at a low reaction temperature, required to perform the reaction for 12-20 hours.

After completion of the reaction, the resulting reaction solution is washed with an aqueous sodium pyrosulphite solution, if necessary, to remove the residual aldehyde compound. In addition, if the carbaldehyde compound of formula (III) accidentally reacted with the amino group of the compound of formula (I) to form a Schiff base, it is preferable to add an ethanolic solution of Girard reagent to the solution. reaction, in order to break down the Schiff base.

The reaction solution that was pre-treated as above is then washed with an aqueous sodium chloride solution and concentrated by evaporation of the solvent under reduced pressure or at atmospheric pressure. To the resulting concentrated solution or solid residue is added methanol, ethyl acetate or butyl acetate, and the resulting mixture is allowed to stand for a certain period of time to be deposited by crystallizing the desired Z isomer. at this time, the presence of a small or very small amount of the secondary E-isomer has no negative influence on the crystallization of the Z-isomer. Thus, the Z-isomer crystals thus obtained are very pure. Therefore, no further purification step (s), such as recrystallization or chromatography, are required to remove the E isomer.

In addition, such an experiment was carried out, as an example of the process according to the first aspect of this invention, in which 7-phenylacetamido3 - [(triphenyl-phosphoranylidene) methyl] -3-cefem-4-carboxylic acid 4-methoxybenzyl ester. , as an example of a compound of formula (I), was dissolved in a mixture of solvents consisting of a mixture of methylene chloride and n-propanol in a mixing ratio (by volume) of 1.0.4, followed by addition to the resulting solution of 4-methylthiazol-5-yl-5-carbaldehyde and the reaction of the resulting mixture at a reaction temperature of -20 "C ± 2 ° C, for 14 hours, with stirring (see example 3 below) . After completion of the reaction, the resulting reaction solution was subjected to high performance liquid chromatography (HPLC) to determine the quantitative ratio of the Z isomer to the E isomer of the 4-methoxybenzyl ester of 7-phenoxyacetamido-3- [2- (4 -methylthiazole-5-yl) vinyl] -3-cefem-4-carboxylic acid, thus obtained in the reaction solution. The conditions for HPLC determination are as follows:

Column: YMCA-312; diameter 6, mm x height 150mm

Mobile phase: 0.05M phosphate-acetonitrile buffer solution (1: 1)

Detection light wavelength: 274 nm.

It was found that the value of the ratio (Z: E) between the surface (Z) below the absorption peak of the isomer Z and the surface (E) below the absorption peak of the isomer E measured in the chromatogram thus obtained was 45.4: 1.0 sample authentic of each isomer Z and E was prepared by another means and HPLC data of these samples were further prepared.

RO 120261 Β1

Considering the HPLC data thus prepared, the value of ratio 1 (Z: E) of 45.1: 1 was established for the ratio of surface Z to surface E defined above, noting that the gravimetric ratio between the isomer Z and the isomer E present in the reaction solution described above 3 obtained in the above experiment was 94.6: 5.4.

By comparison, the above experiment was repeated except that the reaction temperature was set in the range + 25 ° C ± 2 'C instead of the reaction temperature in the range -20 ° C ± 2 ° C. The resulting reaction solution obtained here was determined by HPLC 7 in the same manner as before. After calculating from the numerical data of the ratio (Z: E) between the surface (Z) of the absorption peak of the isomer Z and the surface (E) of the absorption peak of the 9 isomer E, measured in the chromatogram thus obtained in the comparative experiment, it was established that , respectively, the amount of E isomer present in the reaction solution obtained in 11 comparative experiment was considerably higher compared to the amount of Z isomer present here. 13

Although the experiments illustrated above are merely illustrative, the results of the above tests in these experiments may support the fact that the Z isomer may be remarkably preferentially produced relative to the E isomer, according to the process of the first aspect of this invention.

Among others, when the 3-vinyl-3-cefem compound of general formula (IV), obtained 17 by the process according to the first aspect of this invention, contains the residual amino-protecting group and / or the residual carboxyl-protecting group, such protective group 19 can be removed by conventional means. Then, when the desired deprotected product has been routinely recovered from the reaction solution from the aforementioned protection reaction 21, it is still possible to obtain the Z isomer in the form of the high purity deprotection product. 2. 3

Following further investigations, it was found that when the process according to the first aspect of this invention is carried out with the choice as a solvent based on chlorinated hydrocarbon to be used in the solvent mixture of methylene chloride and with the choice as lower alkanol of n-propanol and also when the reaction between compound 27 of formula (I) and compound of formula (III) is carried out in such a solvent mixture of the mixture of the two solvents above mixed in the mixing ratio 29 (by volume) in the range 1: 1-1: 0.28 and is carried out in particular at a temperature in the range -10 ° C to 30 ° C, the amount of Z isomer of the product of formula (IV) thus obtained in the solution of The resulting reaction is considerably larger than that of the isomer E. In addition, it was found that when the reaction solution thus obtained is post-treatment for recovery 33 mentioned below, the Z isomer crystals thus collected can be obtained with high purity and high yield. 35

According to a second aspect of this invention, there is thus provided a process for the preparation of a highly pure 7-N-amino-unsubstituted or substituted-37 3- [2- (4-thiazole-substituted or unsubstituted-5-yl) vinyl isomer. ] -3-cefem-4-carboxylic acid or an ester thereof of formula (IV) above, which comprises the reaction of a 7-N-amino-unsubstituted or substituted-3 - [(trisubstituted phosphorarylidene) methyl acid ] -3-cefem-4-carboxylic acid or an ester thereof with the following general formula (I): 41

RO 120261 îns1 where, R ¹ means a hydrogen atom or an amino-monovalent-protecting group, or R ¹ means a 2- (2-N-aminothiazole-protected or unprotected-4-yl) -2-alkoxyiminoacetyl group with the following formula (II):

where R ⁵ is a hydrogen atom or an amino-monovalent-protecting group and R ⁶ is a hydrogen atom, or R ⁵ and R ⁶ taken together means an amino-divalent-protecting group and R ⁷ is an alkyl group of 1 -4 carbon atoms and wherein R ² means a hydrogen atom, or R ¹ and R ² taken together means an amino-divalent-protecting group and R ³ means a hydrogen atom, a pivaloyloxymethyl group or a group which forms a ester as a carboxyl-protecting group and R ⁴ means an alkyl group of 1-6 carbon atoms or an aryl group, or a compound represented by the following general formula (Γ):

where R ¹ , R ² , R ³ and R ⁴ have the same meanings as defined above, with a 4-thiazole-substituted or unsubstituted-5-carbaldehyde, represented by the following formula (III):

CHO (III) where R ⁸ means a hydrogen atom, an alkyl group of 1-4 carbon atoms, a trifluoromethyl group or a chloro group, in a solvent mixture consisting of a mixture of methylene chloride, chloroform or dichloromethane with n-propanol, mixed in a mixing ratio (by volume) in the range 1: 1 to 1: 0.28, at a temperature in the range -10 ° C to -30 ° C, to obtain thus the reaction solution containing the Z-isomer of 7-Namino-unsubstituted or substituted-3- [2- (4-thiazol-substituted-unsubstituted-5-yl) vinyl] -3-cefem-4 carboxylic acid or an ester thereof of the formula ( IV):

where R ¹ , R ² , R ³ and R ⁸ have the same meanings as above, then washing the reaction solution with an aqueous solution of potassium pyrosulphite, then concentrating the reaction solution, adding to the concentrated solution resulting from methanol or butyl acetate. or a mixture thereof to crystallize from the solution the Z isomer of the compound of formula (IV).

In the process according to the second aspect of this invention, the reaction between cornea, starting material of formula (I) or (I ¹ ) and the carbaldehyde compound of formula (III) can be carried out in the same manner. as for the corresponding reaction in the process according to 3 of the first aspect of this invention. In addition, in the process according to the second aspect of this invention, the Z isomer crystals can be obtained in the crystallization step of the Z 5 isomer of methanol or butyl acetate added to the respective concentrated solution, and the Z isomer crystals thus obtained. they contain only a very small amount of the E. isomer. Thus, the Z 7 isomer thus obtained is in the form of high purity crystals and in most cases does not require any further purification. 9

As is clear from the above, this invention is used in particular for the preparation of 3- (2-vinyl-substituted) -cephalosporin antibiotics and also for the preparation of 11 intermediates used for the synthesis of said cephalosporin antibiotics.

Embodiments 13

The following examples illustrate this invention more concretely, but do not limit the invention to them. In the examples below, HPLC was subjected to evaluate the ratio of these Z and E isomers, either the reaction solution containing the Z isomer and the E isomer of the compound of formula (IV), thus formed, or other solutions. . The conditions used for HPLC determination are the same as those used for HPLC determination described above, which are the following: 19

Column: YMCA-312;

Diameter: 6, Mother x height 150mm 21

Mobile phase: 0.05M phosphate-acetonitrile buffer solution (1: 1, by volume)

Wavelength 23 of the detector light: 274nm.

Example 1. (a) In a heterogeneous reaction medium consisting of 30 ml of chloroform 25 and 30 ml of water, 5 g of 7- (4-acetylaminobenzylidenimino) -3-chloromethyl-3-cefem-4-carboxylate was dissolved. 4-methoxybenzyl, 2.7 g of triphenylphosphine and 1.5 g of sodium iodide. 27

The resulting reaction mixture was reacted under stirring at 32 ° C ± 1 ° C for 2.5 hours. The chloroform layer containing iodide 7- (4-acetylaminobenzylidenimino) -3-29 triphenylphosphonium-methyl-3 The thus-formed 4-methoxybenzyl carfeme-4-carboxylate was then separated from the resulting reaction solution. 31

The chloroform layer thus separated was cooled to 3 ° C ± 1 ”C and then a cold aqueous NaOH solution (containing 0.51 g of NaOH dissolved in 30 ml of water) was added thereto. The resulting mixture was reacted at about 3 ° C for 30 min.

(b) The chloroform layer containing 4-methoxy-benzyl 7- (4-acetylamino-bands! idenimino) -3 - [(triphenyl-phospho-35-ranylidene) methyl] -3-cefem-4-carboxylate, separated from the resulting reaction solution and then dried over magnesium sulfate. 37

The liquid volume of chloroform in the chloroform layer thus dried was adjusted to 54 ml by adding an appropriate amount of chloroform to the anhydrous chloroform layer. The resulting chloroform solution of the respective compound, 3- (triphenyl-phosphoranylidene) methyl-cefem, thus formed, was cooled to -25 ° C ± 2 ° C, to which 21.5 ml of n-propanol was then added. 41

The mixing ratio (by volume) of chloroform to n-propanol present in the resulting solution was 1: 0.4. 43

To this solution was added 9.3 g of 4-methylthiazole-5-carbaldehyde, and the resulting reaction mixture was stirred for 14 h with cooling to -20 ° C ± 2 ° C.

The resulting reaction solution was washed with an aqueous solution of potassium pyrosulphite and an aqueous solution of sodium chloride, under ice-cooling, and then concentrated. To the resulting concentrated solution 47, methanol was added to obtain crystallization of the target product, so that 7- (4-acetyl-aminobenzylidene) crystals (2.51 g; 43.8% yield) were collected.

420-Methoxybenzyl-3- [2-4-methyl-thiazol-5-yl) vinyl] -3-cefem-4-carboxylate. The crystals were dissolved in methylene-acetonitrile chloride, and the resulting solution was analyzed by HPLC under the same conditions as mentioned above. It was thus observed that the ratio between the surface below the absorption peak of the Z isomer and the surface below the absorption peak of the E isomer was 32,3: 1. From the evaluation of this numerical value of the ratio of areas (Z: E), it was found that, respectively, the amount of the E isomer is very small compared to that of the Z isomer.

The ¹ H-NMR data of the above compound obtained in this example are shown below:

¹ H-NMR: δ (CDCl ₃ )

2.18 (3H, d, J = 7.0 Hz)

2.41 (3H, s)

2.24 (1H, d, J = 18.3 Hz)

3.49 (1H, d, J = 18.3Hz)

3.78 (3H, s)

5.10 (1H, d, J = 12.1 Hz)

5.15 (1H, d, J = 12.1 Hz)

5.23 (1H, d, J = 5.1 Hz)

5.41 (1H, d, J = 5.1 Hz)

6.30 (1H, d, J = 11.7 Hz)

6.54 (1H, d, J = 11.7 Hz)

6.79-7.82 (8H, m)

8.58 (1H, s)

8.78 (1H, s)

Example 2. (a) As a starting compound, 2.6 g of 7 - [(Z) -2- (2-tritylaminothiazol-4-yl) -2-methoxyiminoacetamido] -3-chloromethyl-3-cefem-4 was used 4-methoxybenzyl carboxylate. This compound reacted with triphenylphosphine and sodium iodide, in the same way as in Example 1 (a). The resulting reaction product was treated with a cold aqueous NaOH solution in the same manner as in Example 1 (a).

(b) A chloroform layer was thus obtained containing 4 - [(Z) -2- (2-tritylaminothiazol-4-yl} -2-methoxyiminoacetamido] -3 - [(triphenylphosphoranilidene) methyl] -3-cefem-4-carboxylate of 4 Then, this compound, 3- (triphenylphosphoranylidene) methyl-3-cefem reacted with 4-methylthiazzo-5-carbaldehyde in a solvent mixture obtained from chloroform and n-propanol (1: 0.4), to a temperature in the range -20 ° C ± 2 ° C for 14 hours, in the same manner as in Example 1 (b).

Thus, 2.30 g of crystals (80.8% yield) of 7 - [(Z) -2- (2-tritylaminothiazine! -4-yl) -2-methoxyiminoacetamido] -3- [2- (4-methylthiazol-5-yl) vinyl] -3-cephem-4-carboxilatde4metoxibenzil. The resulting product was subjected to HPLC under the same conditions as mentioned above. The results of the HPLC analysis showed that the ratio between the surface below the absorption peak of the Z isomer and the surface below the absorption peak of the E isomer in the chromatogram obtained for the above product was 21.3: 1.

¹ H-NMR: δ (CDCl ₃ )

2.42 (3H, s)

2.24 (1H, d, J = 18.7 Hz)

3.48 (1H, d, J = 18.7 Hz)

3.80 (3H, s)

4.07 (3H, s)

5.09 (1H, d, J = 12.0 Hz)

5.13 (1H, d, J = 12.0 Hz)

5.23 (1H, d, J = 5.1 Hz)

RO 120261 Β1

5.98 (1H, m) 1

6.29 (1H, d, J = 11.7 Hz)

6.59 (1H, d, J = 11.7Hz) 3

6.81-7.71 (19H, m)

8.58 (1H, s) 5

Example 3. As a starting material, 10.5 g of 7-phenylacetamido-3-chloromethyl-3-chemo-4-carboxylate 4-methoxybenzyl was used. The reaction of this cefem compound with the reactants and subsequent treatments of the reaction products was carried out in the same manner as in Example 1 (a) and (b). Thus, 10.2 g of crystals (90.9% yield) of 4-methoxybenzyl 7-phenylacetamido-3- [2- (4-9 methyl-thiazol-5yl) vinyl] -3-cefem-4-carboxylate were collected. .

This product thus harvested was analyzed by HPLC under the same measurement conditions 11 as mentioned above. As a result, it was found that the ratio between the surface below the absorption peak of the Z isomer and the surface below the absorption peak of the E isomer in chromium-13 togram obtained for the respective product was 45.4: 1. From this numerical value, the weight ratio between the Z-isomer and the E-isomer present in the respective product 15 of 17.4: 1 was calculated, corresponding to 94.6: 5.4, by numerical conversion. It can be observed from this that the proportion of the E isomer in the resulting product is extremely small compared to that of the Z isomer.

¹ H-NMR: δ (CDCl ₃ ) 19

2.40 (3H, s)

3.21 (1H, d, J = 18 Hz) 21

3.46 (1H, d, J = 18 Hz)

3.67 (2H, d, J = 3.5 Hz) 23

3.81 (3H, s)

5.06 (1H, d, J = 7.5 Hz) 25

5.07 (1H, d, J = 7.5 Hz)

5.15 (1H, d, J = 12 Hz) 27

5.88 (1H, dd, J = 5 Hz and J = 9 Hz)

6.30 (1H, d, J = 12 Hz) 29

6.56 (1H, d, J = 12 Hz)

6.8-7.4 (9H, m) 31

8.60 (1H, s)

Example 4. 2.8 g of t-butyl 7-phenylacetamido-3-bromomethyl-3- 33 cefem-4-carboxylate was used as starting material. The reaction of this cefem compound with the reagents and subsequent treatments was carried out in the same manner as in Example 1 (a) and (b). Thus, 0.54 g of 35 crystals (yield: 54.3%) of 7-phenylacetamido-3- [2- (4-methylthiazol-5-yl) vinyl] -3-cefem-4-carboxylate were collected. butyl. 37

This product thus harvested was analyzed by HPLC under the same conditions as mentioned above. As a result, it was found that the ratio between the surface below the absorption peak 39 of the Z isomer and the surface below the absorption peak of the E isomer in the chromatogram obtained for the respective product was 29.4: 1. From this numerical value, the weight ratio of the Z-isomer and the E-isomer present in the respective product of 11.5: 1 was calculated, which corresponds to 92: 8 by numerical conversion. It can be seen from this that the proportion of isomer E in the harvested product is extremely small compared to that of the isomer Z. 45

EN 120 261 Β1 ¹ H-NMR: δ _(CDCl3)

1.35 (9H, s)

2.44 (3H, s)

3.18 (1H, d, J = 18.3 Hz)

3.44 (1H, d, J = 18.3Hz)

3.65 (2H, d, J = 2.6 Hz)

5.05 (1H, d, J = 4.8 Hz)

5.87 (1H, m)

6.29 (1H, d, J = 11.7 Hz)

6.61 (1H, d, J = 11.7 Hz)

7.26-7.71 (5H, m)

8.61 (1H, s)

Example 5. (a) 1.1 g of 4-methoxybenzyl 7-amino-3-chloromethyl-3-cefem-4-carboxylate was dissolved, 0.55 g of triphenylphosphine and 0.32 g of sodium iodide in a heterogeneous reaction medium consisting of 6.5 ml of chloroform and 6.5 ml of water. The resulting reaction mixture was reacted at 32 ° C ± 1 ° C for 2 hours. The chloroform layer containing the desired reaction product was separated from the reaction solution thus formed. After cooling the chloroform layer, thus separated, at 3 ° C ± Γ C, a cold aqueous solution of NaOH (containing 0.17 g of NaOH dissolved in 8.6 ml of water) was added to the cooled chloroform layer. the reaction was continued at a temperature of 3 ° C ± 1 ° C, for one hour and 15 min.

(b) A chloroform layer containing 4-methoxybenzyl 7-amino-3 - [(triphenylphosphoranilidene) rnetyl] -3-cefern-4-carboxylate was separated from the resulting reaction solution. The chloroform layer thus separated was dried over magnesium sulfate and then an amount of chloroform was added thereto to adjust the liquid volume of chloroform present in the respective chloroform layer to 12 ml. The resulting solution was cooled to 25 ° C ± 2 ° C and 4.6 ml of n-propanol was then added, followed by the addition of 1.9 g of 4-methylthiazole-5-carbaldehyde. The mixing ratio between chloroform and n-propanol in the resulting reaction mixture was 1: 0.38 (by volume). The reaction mixture was cooled to -20 ° C ± 2 ° C and reacted, with stirring, to -20 ° C ± 2 ° C.

After completion of the reaction, the reaction solution thus obtained was washed with an aqueous solution of potassium pyrosulphite under ice-cooling and then reacted with Girard T reagent at 22'C for one hour after adding 6.7 ml of the solution. ethanol of Girard T reagent (0.67 g). The resulting reaction solution was washed with an aqueous sodium chloride solution and then concentrated. The crystallization of the reaction product was carried out by adding butyl acetate to the resulting concentrated solution. Thus, 0.5 g of crystals (yield: 56.0%) of 7-amino-3- [2- (4-methylthiazol-5-yl) vinyl] -3-caffe-4-carboxylate of 4-methoxybenzyl were collected.

This product thus harvested was analyzed by HPLC under the same measurement conditions as mentioned above. As a result, it was found that the ratio between the surface below the absorption peak of the Z isomer and the surface below the absorption peak of the E isomer in the chromatogram obtained for the harvested product was 31.9: 1. From this numerical value the weight ratio between the Z isomer and the E isomer present in the respective product of 13.3: 1 was calculated, which corresponds to 93: 7 by numerical conversion. It can be seen from this that the proportion of the E isomer in the harvested product is extremely small compared to that of the Z isomer.

¹ H-NMR: δ (DMSO-d ₆ )

2.43 (3H, s)

2.54 (2H, s)

RO 120261 Β1

3.79 (3H, s) 1

5.15 (2H, d, J = 4.3 Hz)

5.22 (1H, d, J = 5.1 Hz) 3

5.32 (1H, d, J = 5.1 Hz)

6.58 (1H, d, J = 12.1 Hz) 5

6.80 (1H, d, J = 12.1 Hz)

9.59 (1H, s) 7

Examples 6-25. (a) 6 g of 4-methoxybenzyl 7-phenylacetamido-3-chloromethyl-3-cefem-4-carboxylate, 3.4 g triphenylphosphine and 1.94 g sodium iodide were dissolved in a heterogeneous reaction medium 9 consisting of 36 ml of chlorinated hydrocarbon solvent as shown in table 1 below and 36 ml of water. The resulting reaction mixture was reacted at 32'0 + 1 ° C for 1.5 h. After confirmation of the disappearance of the starting material, the organic layer was separated from the resulting reaction solution and then cooled to 3 ° C. + 1 ° C. Next, a cold aqueous NaOH solution (containing 0.64 g of NaOH dissolved in 36 ml of water) was added to the cooled organic layer, with which the reaction was continued at a temperature of 15 3'C ± 1 ° C, for 30 min.

(b) After confirmation of the disappearance of the starting material, the organic layer containing 4-methoxybenzyl 7-phenyl-17-acetamido-3 - [(triphenylphosphoranilidene) methyl] -3-cefem-4-carboxylate, separated from the resulting reaction solution and then dried over magnesium sulfate. The organic layer thus dried was cooled to the reaction temperature shown in Table 1.

After cooling, an alkanol-based solvent 21 as shown in Table 1 was added to the respective organic layer so that the added alkanol and the chlorinated hydrocarbon solvent are present in the resulting mixture in certain proportions (by volume), As shown in Table 1, 11.8 g of 4-methylthiazole-5-carbaldehyde were added to the organic phase. The resulting mixture was reacted at a temperature as shown in Table 1 for 14 h. After completion of the reaction, the reaction solution thus obtained was subjected to HPLC analysis in order to determine the ratio of Z-isomer and E-isomer of 7-. 4-Methoxybenzyl phenylacetamido-3- [2- (4-methylthiazol-5-yl) vinyl] -3-cefem-4-carboxylate thus obtained in the respective reaction solution. The conditions used to determine by HPLC analysis 29 were the same as mentioned above.

The reaction conditions used and the experimental results obtained in Examples 6 ~ 25 31 are summarized in Table 1 (a), below. In the table, BtOH indicates butanol, PrOH indicates propanol and MeOH indicates methanol. 33

Comparative Example 1-2.

By comparison, the reaction of triphenylphosphoranylidene-methyl cefem with 4-methylthiazole-5-carbaldehyde as shown in Examples 6-25 was carried out at room temperature (25 ° C ± 2'C) for 14 hours in the same way as in Examples 6-25. After completion of reaction 37, the ratio of the Z isomer to the E isomer present in the reaction solution thus obtained was measured by HPLC analysis in a similar manner. 39

The results of comparative examples 1-2 are also presented in table (b), below. These results from Table 1 (b) clearly indicate that the proportions of 41 Z isomer and E isomer present in the product compound thus obtained are very different, depending on the mixture of solvent used and the reaction temperature used. In particular, if the reaction is carried out at a temperature of -20 ° C ± 2 ° C, the ratio of the surface of the isomer Z to the isomer E below the absorption peak in the HPLC chromatogram of the reaction product 45 may also reach values such that the surface of the Z isomer was 20 times, or greater and sometimes 30 times or greater than the surface of the E. isomer. Accordingly, the processes of this invention may obviously lead to the selective preparation of the Z isomer. 49

RO 120261 Β1

Table 1 (a)

Nr. ex. Solvent mixture (mixing ratio, by volume) Reaction temperature ('C)' The ratio of the surface (Z: E) below the absorption peaks of the Z and E isomers in the HPLC chromatogram of the reaction solution 6 CH ₂ Cl ₂ -BtOH (1: 3) + 3'012'0 14.8: 1 7 CH ₂ Cl ₂ -BtOH (1: 1) + 3'012'0 16.9: 1 8 CH ₂ Cl ₂ -i-PrOH (1: 1) + 3'012'0 17.5: 1 9 CH ₂ Cl ₂ -n-PrOH (1: 1) + 3'012'0 17.9: 1 10 CH ₂ Cl ₂ -n-PrOH (2: 1) + 3'C + 2'C 19.9: 1 11 CH ₂ Cl ₂ -n-PrOH (4: 1) + 3'012'0 18.7: 1 12 CH ₂ CI ₂ -t-BuOH (4: 1) + 3'012'0 16.9: 1 13 CH ₂ Cl ₂ -BtOH (2: 1) -20 + 2 19.9: 1 14 CH ₂ Cl ₂ -n-PrOH (3: 2) -20 + 2 19.2: 1 15 CICH ₂ CH ₂ CI2-n-PrOH (2: 1) -20 + 2 16.2: 1 16 CH ₂ Cl ₂ -n-PrOH (7: 2) -20 + 2 20.2: 1 17 CH ₂ Cl ₂ -n-PrOH (3: 1) -20 + 2 21.6: 1 18 CH ₂ Cl ₂ -n-PrOH (2: 1) -2012 23.5: 1 19 CH ₂ Cl ₂ -BtOH (2: 1) -2012 25.8: 1 20 CH ₂ Cl ₂ -n-PrOH (5: 2) -20 + 2 28.8: 1 21 CHCI ₃ -PrOH (2: 1) -20 + 2 25.0: 1 22 CHCI ₃ -PrOH (5: 2) -20 + 2 31.0: 1 2. 3 CHCI ₃ -PrOH (3: 1) -20 + 2 29.8: 1 24 CHCI ₃ -PrOH (7: 2) -2012 26.8: 1 25 CHCI ₃ -PrOH (4: 1) -20 + 2 27.0

Table 1 (b)

Nr. ex. Solvent mixture (mixing ratio, by volume) Reaction temperature ('C) (Z: E) 1 CH ₂ Cl ₂ -MeOH (1: 8) 2'0 25'0 + 4.2: 1 2 CH ₂ Cl ₂ -BtOH (1: 3) 25'012'0 8.0: 1

Industrial applicability

As can be clearly seen from the preceding paragraphs, it is found that according to the process of this invention, when the 3- (2-vinyl-substituted) -cefeme compound is to be obtained by using the Wittig reaction, the Z isomer of said cefem compound, which is preferred ,

EN 120261 Β1 can be produced in a considerably larger proportion than that of the E isomer and with a high yield. The processes of this invention can be easily and efficiently applied. The target product obtained by the processes of this invention contains only an extremely small amount of the E isomer, in comparison with the desired Z isomer. The processes according to this invention can be used to obtain a 3- (Z) - (2-vinyl-substituted) -cephalosporin antibiotic, excellent as an antibacterial agent, or to obtain intermediates used in the synthesis of said antibiotic.

Claims (1)

1. Process for selective preparation of the Z-isomer of a 7-N-unsubstituted or substituted-amino-3- [2- (4-thiazol-unsubstituted or substituted-5-yl) vinyl] -3-cefem-4-carboxylic acid or 11 an ester thereof represented by the following general formula (IV): (IV) wherein, R ¹ means a hydrogen atom or a monovalent protecting group of the amino group, or R ¹ means a 2- (2-N-) group aminothiazole-protected or unprotected-4-yl) -2alkoxyiminoacetyl having the following formula (II):